Often, compounds are mixed together to create a new or desired result. For example, buffers, chemicals and other compounds are often combined to create process intermediates in downstream processing of biologics. For example, in some formulations, it is common to mix together various solutes. Solutes are mixed typically in large vessels, which utilize impellers located within the vessel, driven by electric motors. Impellers are typically designed to be used with a specific vessel size and shape. The size, shape and speed at which the impeller turns all factor into determining how quickly the compound will mix.
In some embodiments, the mixing combination is liquid/liquid, where one liquid is mixed into a second liquid. Common examples are the introduction of a base or an acid into a solution. Another specific combination is dissolution of a solute soluble in a particular solvent. In both scenarios, it is imperative that the two materials are completely mixed. For example, incomplete mixing of a base into a solution may leave the volume of fluid nearest the entry point of the base at a higher pH than the rest of the solution, thereby impacting the homogeneity of the solution.
Since it is imperative that the solution be homogeneous, developers often spend significant time determining the required mixing time and mixing methodology so that the homogeneity of the solution is uniform. One way to determine this mixing time is through empirical testing. For example, FIG. 1 shows the typical pH response of a solution to which a base, such as NaOH, has been added at the top of the vessel. Line 10 shows the pH of the solution near the top surface. Note that the pH quickly rises, as the base has added near the pH probe. Since the base was added near the probe, the measured pH actually exceeds the resulting pH (indicating a non-uniform concentration of base) until the base is thoroughly mixed. The vertical lines, at approximately 3 seconds and 19 seconds are used to delineate the time required for the top surface to reach the proper pH level. Line 20 shows the pH of the solution near the bottom of the vessel. Since the base has added near the top, it takes some time until the base reaches the bottom probe. This explains the lag in the response seen in line 20, with respect to line 10. The pH begins to increase at about 10 seconds and mixing is completed at about 26 seconds. Lines 30 and 40 represent a second test using the same configuration, which yielded similar results. Mixing time is determined as the time between the start of the change in the response curve and the time at which the top and bottom curves were both within 5% of the steady state value. In this specific example, the mixing time is about 16 seconds for both runs.
In many cases, when developing new solutions, developers utilize very small batch sizes. Once the developers are assured that the formulation is correct, the solution enters the next phase. This may be scaled up for implementation into the remaining downstream processes, or to begin testing of the solution as a final product. This testing may involve viability and usability of the solution as a final product, patient tests if it is a pharmaceutical, or official governmental review, such as by the FDA to ensure the product meets the required specifications. Once the testing has been approved, the solution moves from the developmental stage to the manufacturing stage for implementation into production stage.
In the production stage, the uniform solution is produced in much larger volumes. Typically, this necessitates the need for larger vessels to be used in the manufacture of the solution. However, the processes that were originally used to create the smaller batches may not always suitable for longer containers nor does the mixing process respond in a similar manner to that of a smaller scale mixing.
Often, the parameters, such as mixing time, for a small vessel cannot be easily scaled to accommodate a large vessel. For example, the mixing time does not scale linearly with vessel capacity. This results in uncertainty in the manufacturing stage, non-reproducibility of the process (hampering validation efforts), and may significantly increase the amount of time to verify the satisfactory completion of the processing time. It would be advantageous if there were a method of determining mixing time for a larger vessel based on predefined known parameters, such as vessel size and impeller RPM. Furthermore, it would be beneficial if this process allowed a verified and previously defined process used with a smaller vessel to be predictably scaled up to a larger vessel.